This month, I’d like to address an issue that often arises in the minds of parents whose children have been newly diagnosed with NF1. These parents often ask when they should be concerned about an issue or symptom that they notice in their child. I don’t think parents should assume the task of being their child’s doctor and become hypervigilant about every potential issue. Instead, parents have the important role and responsibility of nurturing and caring for their child. However, it’s natural for parents to experience anxiety about possible complications of NF1, and we do want parents to be alert to any potentially serious complication that may develop. The key is in separating everyday aches and pains from important symptoms, and the central question becomes:  What are the complications that, if detected early, would allow for better outcomes for children with NF1?

Optic Glioma

A tumor of the optic pathway, or optic glioma, occurs in approximately 15% of children with NF1. These tumors usually occur early in life, between the ages of 18 to 24 months. While more than half of children with optic glioma have no symptoms, some children experience vision loss, usually between the ages of 2 to 6 years. Because very young children don’t complain of vision loss, the early presentation of these problems can be subtle. Some signs of possible visual impairment include: tripping over objects or having difficultly navigating physical obstacles; becoming fearful of walking down stairs; and holding objects closer than normal or sitting closer to a screen, such as a television or computer. While we recommend yearly eye exams for children with NF1, parents who recognize these possible signs of vision loss should make an appointment for an evaluation with an NF specialist or pediatric ophthalmologist.

Physical Growth

A physical feature that is common for children with NF1 is that head size tends to be larger than average. However, a sign of concern would be if the size of the head crossed percentile lines as it grew or became noticeably larger in a relatively short period of time. Also, vomiting and lethargy could be a sign of obstructive hydrocephalus, a condition of increased brain fluid pressure that is rare, but more common in people with NF1 and usually occurs in childhood or young adulthood.

Also regarding physical growth, some degree of short stature is common among children with NF1. Slow weight gain is also common, although falling off the growth curve or crossing percentile lines are a cause for concern that requires further evaluation. In some cases, a brain stem tumor or optic glioma can affect the functioning of the hypothalamus where appetite is controlled, resulting in weight loss.

Plexiform Neurofibromas

These tumors, which occur deep in the body and involve large branches of multiple nerves, are usually noticed in the first year of life. They appear as a painless soft tissue swelling of the arm, leg, or around one or both eyes or on the face. Plexiform neurofibromas are believed to be congenital in most cases, although they are not easy to see at birth. Swelling of the upper eyelid in the early years of life could be a sign of a plexiform neurofibroma around the eye, which can grow rapidly in childhood and cause significant disfigurement and interference with vision.  Enlargement of an arm or leg can also be an early sign of plexiform neurofibroma.   

Bone Dysplasia

This problem is an abnormality of a long bone, usually involving the tibia in the leg but also sometimes affecting the fibula as well as bones in the arms. Bone dysplasia sometimes presents as bowing of a leg in infancy, although this can be difficult to detect early because most infants have some normal leg bowing. By the time a child can stand, one can usually determine if dysplasia is present. An X-ray is performed to confirm the problem, and the child is referred to an orthopedist for treatment with a leg brace to prevent fracture. If a fracture does occur, it can be difficult to treat, which makes early detection of this problem important.

Developmental and Cognitive Issues

Some children with NF1 exhibit low muscle tone, which results in muscles that are less firm and seem weaker than normal.   This problem tends to improve over time, but it may evolve into some degree of poor coordination in adolescence and adulthood. Also, learning problems are present in approximately 50% of children with NF1, although this issue may not become apparent until the child has reached school age.  Children with NF1 may exhibit problems in maintaining attention, hyperactive behavior, and social immaturity.  In some, speech articulation may be affected.  Sudden onset developmental delay is not common in children with NF1.  If a child is failing to reach developmental milestones or displays signs of learning or cognitive problems, this is a cause for concern and further evaluation. 


I have mentioned the occurrence of headaches in children with NF1 in previous blogs.  Most typically these occur intermittently and may be associated with nausea, stomach aches, and vomiting.  These signs are suggestive of migraine, which seems to be more common in children with NF1 than in the general population.  Another cause of headaches in children with NF1 is Chiari malformation, in which the base of the brain extends below the foramen magnum, which is the space in the skull where the spinal cord connects to the brainstem.  This is also more common in children with NF1 than in the general population.  Many parents of children with NF1 and headaches worry that the headaches could be a sign of brain tumor.  For a brain tumor to cause headaches it requires that the tumor cause increased fluid pressure in the brain.  If this does happen, the headaches are usually severe, may wake the child from sleep, and are associated with severe vomiting.  A careful physical exam would reveal increased pressure on the optic nerve visible in an eye exam, and would be followed up with an MRI scan.  Fortunately, I find that this is an uncommon cause of headaches in children with NF1.
In news related to the UAB NF Program, I’d like to mention that that Department of Defense NF Research Program has issued a request for grant applications (RFAs) from investigators to support innovative, high-impact NF research.  Several of our faculty members have submitted proposals, and more updates will follow as the process moves forward.

Pain Related to NF1

In this month’s post, I think it would be helpful to discuss the issue of pain in the context of NF, other than headaches, which have been covered previously. Individuals with neurofibromatosis type 1, the most common form of NF, can sometimes experience pain related to the presence of neurofibromas, benign tumors that can grow on nerves throughout the body.  While neurofibromas are not typically painful, some people have pain associated with these tumors that may take a variety of forms. Cutaneous neurofibromas, which appear on the surface of the skin, can sometimes result in pain due to an event that causes pressure on the tumor, such as hair brushing.  These tumors can also become infected, which can be painful.  Subcutaneous neurofibromas, occurring under the skin, can be nodular and are usually pea-sized to marble-sized. Though not typically painful most of the time, they can be tender to the touch or pressure such as hair brushing or lying down. Subcutaneous neurofibromas on the scalp can also serve as trigger points for headaches by internally pressing on nerves and surrounding structures, causing pain.

Plexiform neurofibromas occur deep inside the body and are usually not painful unless causing pressure on internal structures. There are instances in which they can press on nerve roots, resulting in significant pain. Some individuals with NF1 develop a condition call dural ecstasia in which there is a ballooning of the membranes surrounding the spinal cord that can put pressure on surrounding nerves, resulting in pain in the lower back or legs.   This can be a very difficult condition to treat surgically, and may result in chronic pain.

Some adults with NF1 may also experience exquisite pain with pressure applied at the tips of fingers and toes due to the presence of glomus tumors that occur under the nail beds. Fortunately, this pain can be eliminated by removing these tumors surgically; however, many adults don’t associate this pain with NF and therefore don’t seek treatment. It’s important for patients and clinicians to be alert to this type of pain so that surgery can be performed if needed.

Malignant peripheral nerve sheath tumors, which occur in 10% of people with NF1, cause a nagging, unremitting pain that becomes worse over time. It’s important to recognize this type of pain so that an imaging study, such as an MRI and PET scan, can be performed to identify the tumor and recognize its malignant potential.  For this reason, people with NF should be alert to any unexplained and persistent pain.

Pain Related to NF2 and Schwannomatosis

Chronic pain can occur in individuals with neurofibromatosis type 2 due to nerve root compression by one of the two types of tumors associated with the condition, meningiomas and schwannomas.

People with schwannomatosis, the third distinct type of NF, usually experience excruciating pain, which is a hallmark of the condition. Surgical removal of schwannomas usually relieves pain, although surgery is not always feasible due to the location of the tumors. Interestingly, the pain tends to be out of proportion with the number and size of tumors. Small tumors can be surprisingly painful, which may indicate there is something inherent in the tumor that causes pain.

Pain Management and Signs to Seek Treatment

In mild instances of NF-related pain, over-the-counter medications, such as Ibuprofen, are usually indicated and can be effective. Pain due to nerve compression or dysfunction sometimes responds to the medicine gabapentin or other similar medications.  Also, pain management programs can be helpful in dealing with chronic pain for which there is not a treatment option available. These programs have extensive experience in helping patients achieve symptom relief while avoiding addictive drugs when possible.

In conclusion, it’s important for individuals with NF to understand the signs of when to seek treatment for pain, including: chronic or nagging pain that gets worse over time; neurofibromas that become noticeably larger; pain with pressure applied to the tips of fingers and toes; and localized pain, which may be an indication of nerve root compression.
2017 NF Conference in Washington, DC

Last month, nearly a dozen colleagues from UAB attended the 2017 NF Conference in Washington, DC.  This international conference, organized by the Children’s Tumor Foundation, began in the 1980s with the original purpose of promoting the sharing of data to assist in mapping and the ultimate identification of the NF genes.  When these goals were accomplished for NF1 and NF2, the meeting gradually evolved to an annual international research conference. The event now serves as the global flagship scientific forum where more than 300 participants from a range of scientific and clinical backgrounds gather annually to build consensus and foster collaboration for advancing basic, translational, and clinical research focused on improving outcomes for all forms of NF. The four-day conference features a series of poster presentations summarizing research, invited lectures, and platform presentations.  Many of the speakers are from outside the NF field, broadening the scientific input into the study of NF. 

While I’m not certain whether our UAB group was the largest contingent at the meeting, we were certainly among the largest groups in attendance. Several of us from UAB gave talks from the platform and most had poster presentations. A poster developed by Bob Kesterson, PhD, a professor of genetics and research scientist in our program, won the prize for best poster at the conference. Dr. Kesterson’s poster demonstrated how complementary DNA (cDNA) is now being used to provide a tool for assessing whether a mutation affects the function of the NF1 gene.  This approach will be useful in determining whether some variants of unknown significance in the NF1 gene are actually disease-causing.  It will also be used to determine whether skipping some part of the gene that contains a mutation will be tolerated (see last month’s blog on exon skipping).  Dr. Kesterson was invited to give a brief talk on his research, and his award and recognition was an honor for him and our program.  As I discussed in last month’s blog, there is an increasing focus within the NF scientific community on the development of genomic-guided therapies that will restore function to mutated genes. While this approach is already being used to develop potential treatments for other diseases such as cystic fibrosis and muscular dystrophy, it is receiving greater focus and attention from other scientific communities, including NF.  We at UAB are recognized as the pioneering group in genomic-guided therapeutics within the context of NF, and we look forward to continuing our role as a leader in developing initiatives that will advance this promising avenue of potential treatment for NF.

NF Clinical Trials Consortium and Commonly asked Questions

Every six months, the NF Clinical Trials Consortium Steering Committee meets to discuss plans for upcoming clinical trials.  Our most recent meeting was held in December in Baltimore with staff members from the Department of Defense (DoD) in attendance. This was the first steering committee meeting held since we learned of renewed funding, and we are preparing to launch the next round of clinical trials. Persons with NF often inquire about which clinical trials are available and if they can participate.  Sponsored by the US government, the Web site provides information about all clinical trials categorized by condition.  The federal government requires trials to be registered and to include detailed information on the site about eligibility criteria, site location, primary outcome measures, and other information.

In the past, clinical trials were not always forthcoming about outcome information, especially if the trial did not prove to be effective. Now it is mandated that outcome information be posted on the site for trials that have been completed.

We also receive occasional questions regarding the preliminary outcome of a clinical trial that is ongoing. We’re unable to provide any information about the preliminary findings of a clinical trial until the final data have been received. Typically, the investigators are not privy to the data because there is concern about possibly biasing the study. We therefore can’t answer the question of “What are you seeing so far?” A Data Safety Monitoring Board appointed to oversee a trial reviews the data for the ongoing study. In some cases, the trial is so effective that it is discontinued early. In other cases, the board may have data to indicate that the trial is not working or that side effects are too serious, and they will stop the trial.  Another frequent question from patients is whether they can participate in a trial at a distance, or even from outside the country, instead of at the site where the trial is being conducted. Depending on the trial design, sometimes this is possible, though most times challenges exist that may not make it possible. If a medication is part of a trial, it is required that participants receive the medication at the site of the trial. Also, there are often routine screening tests that must be performed on site. Because it is sometimes possible to participate in a clinical trial from another location, it’s best to contact the staff conducting a particular trial to learn about participation requirements.  Contact information is provided on